Fluorine-substituted amino acids have application in peptide-based drug design and protein engineering and also demonstrate application in PET imaging for diagnosis of cancer. Since 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was successfully developed as a positron emission tomography (PET) tracer and used for routine cancer imaging, designing and developing fluorine-18 radiolabeled agents for diagnosis of various diseases has emerged as a very active research area. See, e.g., Mercer, J. R., Molecular imaging agents for clinical positron emission tomography in oncology other than fluorodeoxyglucose (FDG): applications, limitations and potential. Journal of Pharmacy & Pharmaceutical Sciences 2007, 10, (2), 180-202; Couturier, O.; Luxen, A.; Chatal, J.-F.; Vuillez, J.-P.; Rigo, P.; Hustinx, R., Fluorinated tracers for imaging cancer with positron emission tomography. European Journal of Nuclear Medicine and Molecular Imaging 2004, 31, (8), 1182-1206.; and Miller, P. W.; Long, N.J.; Vilar, R.; Gee, A. D., Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography. Angewandte Chemie, International Edition 2008, 47, (47), 8998-9033.
The mechanism of cancer imaging by FDG is based upon the avidity of tumor cells toward energy source—glucose, i.e., the increased glycolysis in tumor cells. Recent reports suggest that glutamine (NH2C(O)CH2CH2CHNH2C(O)OH), Gln) may also be a source of metabolic energy for cells under stress—glutaminolysis. Wise, D. R.; Deberardinis, R. J.; Mancuso, A.; Sayed, N.; Zhang, X. Y.; Pfeiffer, H. K.; Nissim, I.; Daikhin, E.; Yudkoff, M.; McMahon, S. B.; Thompson, C. B., Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008. Accordingly, a need exists to develop Gln and its analogs as metabolic tracers for studying increased tumor metabolism.
There is interest in synthesizing the four diastereomers of 18F-radiolabeled 4-fluoro-L-glutamines (4-FGln) ([18F]1, 2, 3, and 4) and further assessing their biological properties in various types of tumor cells.

In order to validate the preparation of [18F]1-4, however, a practical synthesis of the nonradioactive molecules, the so-called “cold standard,” first needs to be achieved. Attempts to synthesize various stereospecific fluorinated α-amino acids (F-α-AA) have been reported recently. Dave, R.; Badet, B.; Meffre, P., gamma-Fluorinated analogs of glutamic acid and glutamine. Amino Acids 2003, 24, (3), 245-261. Tolman, V.; Sedmera, P., Chemistry of 4-fluoroglutamic acid. Part 3. Preparation of the diastereomers of 4-fluoroglutamine and 4-fluoroisoglutamine. An enzymatic access to the antipodes of 4-amino-2-fluorobutyric acid. Journal of Fluorine Chemistry 2000, 101, (1), 5-10. Those syntheses are summarized below in Schemes 1 and 2:


The sequence set forth in Scheme 1 only provides 4-fluoroglutamine as a mixture of four diastereomers, starting from a mixture of 4-fluoroglutamic acids. Diastereomers of 4-fluoroglutamic acid can require up to 11 steps to prepare. The sequence set forth in Scheme 2 starts with a racemic mixture of either erythro or threo 4-fluoroglutamic acids. The racemates are then converted to racemic erythro or racemic threo 4-FGln. Single isomers cannot be prepared according to the method of Scheme 2. Interestingly, Dave, et al. state that “It is worth noting that the same transformation [of Scheme 2] have not yet been applied to the synthesis of enantiomerically pure 4-fluoroglutamine despite the available procedures for the preparation of all four stereomers of 4-fluorogluamic acid.
WO2008/052788 describes the preparation of diastereomeric mixtures of 4-fluoro-L-glutamine, prepared by a metal-catalyzed synthesis using a nickel complex of a glycine-containing Schiff's base and (S)-2-[N—(N-benzylpropyl)amino]benzophenone (BPB) and 3-bromobut-3-enoic acid methyl ester:
WO2008/-62799, Examples 1 and 2.
Nevertheless, the synthesis of single isomers of each of the four diastereomers of 4-fluoroglutamine has yet to be reported. Moreover, considering that the ultimate goal is to synthesize a radioactive compound, a synthesis that introduces the fluorine atom at a late stage, in contrast to the sequences set forth in Schemes 1 and 2, is advantageous due to the short half life of 18F atom (t1/2=109.7 min).